Magnetic Resonance Techniques in the Evaluation of the Newborn Brain

NEUROLOCIC DISORDERS IN THE NEWBORN PART I

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RESONANCE TECHNIQUES IN OF

NEWBORN BRAIN Petra S. Huppi, MD, and Patrick D. Barnes, MD

With the advances in reproductive medicine and neonatal intensive care, clinicians now are confronted with an increasing number of high-risk newborns who suffer from considerable neurologic morbidity that often is associated with lifelong handicaps. New diagnostic tools are therefore needed to assess brain development, detect early brain injury, and monitor interventions aimed at minimizing or preventing irreversible brain injury. MR imaging techniques are attractive for use in newborns because of their resolving power andrelative noninvasiveness and the availability of magnet-compatible vital monitoring and support devices. The ability of MR imaging to provide detailed structural and metabolic and functional information without the use of ionizing radiation is unique when compared with ultrasonography (US), CT scanning, and nuclear medicine including single-photon emission computed tomography (SPECT) and positron emission tomography (PET). In order to understand the potential applications and limitations of MR imaging, this article first provides some of the relevant basic physical and biologic principles of this technology. This is followed by a presentation of the important aspects of normal brain development that have to be taken into account when discussing pathologic changes during the newborn period. An outline then is provided regarding some of the established and developing uses of MR imaging and MR spectroscopy in the diagnosis and management of neonatal neurologic disorders.

From the Joint Program in Neonatology (PSH) and the Division of Neuroradiology, Department of Radiology (PDB), Harvard Medical School and Children's Hospital, Boston, Massachusetts

CLINICS IN PERINATOLOCY VOLUME 24 • NUMBER 3 • SEPTEMBER 1997

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BASIC PRINCIPLES OF MR TECHNIQUES MR Imaging Structural MR Imaging

MR imaging is the standard terminology used for MR imaging; MR spectroscopy is used for spectroscopy. 98 Both MR imaging and MR spectroscopy are possible because of the intrinsic magnetic properties of atomic nuclei in the body that possess an odd number of nucleons (protons and neutrons). These nuclei include lH, 14N, 31P, 13C, and 23Na. Hydrogen (lH) is the most abundant and strongest of the nuclei (e.g., in water and fat) and is involved in most MR procedures. These nuclei spin about their own axes, produce a nuclear angular momentum, and align with an externally applied magnetic field. This angular moment produces a magnetic field about the nucleus and is termed the nuclear magnetic dipole moment (MDM). We, therefore, can picture the MDM of each hydrogen nucleus, for example, as a tiny bar magnet within the strong magnet of an MR imaging system that spins and aligns parallel with the main magnetic field along the long axis of the magnet. The magnetic field causes the MDMs to wobble, or twist like a top, along the direction of the magnetic field. The precession frequency (w) of the MDM in a magnetic field is given by the Larmor equation w = -yf3, where w is the frequency in revolutions per second, 'Y is the gyromagnetic ratio for the specific nucleus, and f3 is the strength of the magnetic field in Tesla. The Larmor equation states that when a patient is placed in the magnetic field, every nucleus ("{)with a nonzero angular momentum has an MDM precessing simultaneously at a specific rate (w) depending on the magnetic field (f3) it experiences. All aligned MDMs of one type of nucleus in a volume of tissue form a sum vector representing the local net magnetization. In the example of hydrogen (lH), whose nucleus contains a single proton, this is the magnetization formed by the MDMs of the lH protons in the patient. In a magnet of 1.5 Tesla (f3), the Larmor frequency (w) of precession for Hl ("{ = 42.58 MHz/T) is approximately 64 MHz. To selectively detect a specific nucleus, for example the lH proton as used in MR imaging, we use radiofrequency (RF) pulsing. When the RF pulses are applied at the Larmor frequency by an RF transmitter coil oriented perpendicular to the long axis of the main magnetic field, the local magnetization of the MDMs precess and align with the axis of the magnetic field of the RF coil. This process is known as excitation and involves the phenomenon of "resonance," which refers to the preferential absorption of energy by an oscillating system at its intrinsic frequency. By applying the resonance frequency for lH, the hydrogen MDMs are selected over all other species of precessing MDMs. If we wish to excite or perturb the magnetizations of 31P or 14N, we would simply substitute their gyromagnetic ratios into the Larmor equation and apply the RF pulses at their respective resonant frequencies. The excitation of the local magnetizations of the MDMs in tissue by RF pulses creates magnetization in the transverse plane, and this transverse magnetization can be detected by an RF receiver coil. Relaxation refers to the process that occurs after the termination of the transmitter RF pulses such that the local magnetizations of the MDMs realign or relax from the transverse magnetization state to the original longitudinal magnetization state. A small electromagnetic signal, the so-called free induction decay (FID), then is detected by the receiver RF coil. The signal amplitude decays with a time decay of the FID since curve (T2*) ranging from a few milliseconds to a few seconds, depending on the nucleus and its magnetic environment. Because the FID signal often is too short

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and too weak to measure, one or more additional RF pulses are applied in the transverse plane to produce one or more echoes. This allows measurements of longitudinal relaxation (Tl) and transverse relaxation (T2). Tl (spin-lattice) relaxation refers to the realignment of the lH spins with the main magnetic field (recovery of longitudinal magnetization). It involves the exchange of energy between the realigning protons (lH spins) and their molecular environment (lattice) as determined by molecular size, structure, motion, and collision. T2 (spin-spin), or transverse, relaxation refers to the loss of transverse magnetization owing to the magnetic interaction between protons (precessing lH spins) as influenced by inhomogeneities in the local tissue magnetic fields. These magnetic-field variations cause changes in the precession frequencies and phases of the protons. This dephasing and loss of coherence of the protons results in the decay, or loss, of the MR signal as measured by one or more echoes generated by refocusing, or rephasing, RF pulses. Proton density, or spin density (i.e., concentration), also affects MR signal intensity. To obtain an image, a pulse sequence is used. A pulse sequence consists of a series of RF pulse cycles with the repetition time (TR) being the interval between two successive pulse cycles and the echo time (TE) being the interval from the RF pulse to the measurement of the MR signal. This is the most common basic pulse sequence method, the spin-echo technique. Other basic pulse sequence techniques are the inversion recovery and the gradient-echo methods. In general, with short TRs (e.g., 600 msec) and short TEs (e.g., 20 msec), Tl-weighted images are generated. Longer TRs (e.g., 3000 msec) with short TEs (e.g., 20 msec) are used to produce proton density weighted images. With long TRs (e.g., 3000 msec) and long TEs (e.g., 100 msec), T2-weighted images are generated. An MR imaging acquisition consists of a set of planar images acquired through a volume of tissue, such as the brain. Hence, an MR imaging acquisition is a three-dimensional process and requires spatial encoding of the signal intensities along the x, y, and z coordinate axes. Magnetic-field gradients are superimposed on the main magnetic field and applied along the three axes to provide spatial localization. The signal produced is a composite representing a two-dimensional pixel grid, or matrix, within a slice. The image of a slice is generated by a mathematical transformation, the two-dimensional fast Fourier transform, and consists of signal intensities along a gray scale from dark (low intensity) to bright (high intensity). Several MR imaging pulse sequence techniques have been used effectively in the structural assessment of the newborn brain. These include the fast spinecho [e.g., fast spin echo (FSE), rapid aquisition recalled echo (RARE)], most useful for generating T2-weighted and proton density contrast; the inversionrecovery (IR) method to produce high-contrast Tl-weighted images; and the fast gradient-echo method [e.g., gradient echo (GE), spoiled gradient recalled echo (SPGR), gradient recalled acquisition at steady state (GRASS)] to provide Tl, T2, and T2* contrast. Echo planar imaging (EPI) refers to a class of new ultrafast techniques. The gradient-echo and EPI techniques use gradient pulses rather than RF pulses for echo generation. These allow faster imaging, including functional imaging. Postprocessing Techniques

MR imaging has proved to be a revolutionary diagnostic radiologic tool due to its high sensitivity and excellent discrimination of soft tissues. It provides rich information about morphology in healthy and diseased tissue. Quantitative information about the structural content of the brain, however, is needed to detect subtle changes in development. Such quantitative methods recently have

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been devised and applied as postprocessing computer techniques for conventional MR imaging. 35 • 77• 81 Volumetric analyses of MR imaging data sets are achieved by segmentation of the imaged volume into tissue types. Segmentation is the process whereby contours are constructed that partition the brain into representative structures of interest depending on their signal intensity (e.g., gray matter, myelinated white matter, unmyelinated white matter, and CSF). Such tissue segmentation is achieved by applying statistical classification methods to the signal intensities in conjunction with morphologic image-processing operations. 23• 92

Functional MR Imaging

Structural MR imaging, primarily using spin-echo and inversion recovery techniques, has widely proven its potential for identifying normal and pathologic brain morphology. The further development of gradient-echo and EPI methods for fast and ultrafast imaging of brain function has generated excitement because of the potential for providing insights into brain physiology in normal and diseased states. Two of these functional MR imaging methods are diffusion-weighted imaging and perfusion imaging. Diffusion-Weighted MR Imaging

Diffusion-weighted MR imaging (DWI) measures the self-diffusion of water molecules. In biologic tissues, water diffusion is not truly random because membranes and macromolecular interactions present barriers to diffusion. Therefore, the self-diffusion of water in tissue is referred to as "apparent diffusion" and its rate as the apparent diffusion coefficient (ADC). The general principle underlying the measurement of diffusion with MR imaging is to add a pair of strong gradient pulses along a single axis to the otherwise standard pulse sequence. Where there is a net movement, or translation, of protons between the applications of the diffusion-sensitizing gradients, these spins are not perfectly rephased and their signal is attenuated. This signal attenuation is also dependent on the strength, or b value, of the diffusion-weighted gradients. The ADC is related inversely to the b value. ADC maps of the brain can be calculated to show areas of different water diffusivity. On DWI at high b values, regions of lower ADC appear hyperintense relative to regions of higher ADC. The normal mature brain parenchyma, therefore, appears high intensity relative to the CSF. On the calculated images, or ADC images, the gray scale intensities are inverted. DWI and ADC maps also may depend on the direction along which the diffusion gradient is applied. The variations in the diffusion of water molecules in different spatial directions (e.g., parallel versus perpendicular to white matter tracts) is known as diffusion anisotropy. Because of the microscopic structure of tissues, the diffusion is anisotropic and measurements in three orthogonal directions must be obtained to construct a true diffusion map (trace of the diffusion tensor) and to obtain information about the differences in the diffusion anisotropy of tissues. 10 Diffusion tensor MR imaging can be used to estimate an effective diffusion tensor (D) in each voxel and to calculate its principal directions and diffusivities. Quantitative indices derived from the diffusion tensor allow measurement of apparent diffusion and diffusion anisotropy that ultimately depend on microstructural tissue development. The main interests in the

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clinical use of DWI is in the evaluation of brain maturation and the detection of cerebral ischemia. Perfusion MR Imaging Perfusion MR imaging techniques provide measurements of blood volume and transit time and blood flow as relative measures of brain function. The two strategies that have been applied most often to clinical conditions and scientific questions are based either on induced changes in intravascular magnetic susceptibility (T2*) or on tagging inflowing arterial spins. The susceptibility-based techniques use either injected paramagnetic contrast agents (e.g., gadoliniumDPTA) or endogenous changes in the concentration of an intrinsic paramagnetic molecule (e.g., deoxyhemoglobin) to induce intravascular susceptibility changes related to brain perfusion. 11 • 56 • 68 • 73 The diffusion of water through these gradients leads to a loss of phase coherence and thus a decrease in T2* signal intensity. 72 The amount of signal loss can be quantified and is directly proportional to cerebral blood volume. Dynamic gadolinium-enhanced susceptibility weighting has been used to define regions of ischemia. When compared with normally perfused brain, the degree of signal reduction in the ischemic areas is reduced markedly within minutes of the insult. These perfusion abnormalities are evident before changes occur on T2-weighted MR imaging. 96 Blood-flow imaging with MR imaging by spin labeling of the arterial input to a slice is a more direct assessment of the cerebral blood flow. 33 • 97 These techniques also have been used to assess functional localization within the brain as related to local cerebral perfusion changes during sensory, motor, or cognitive activation. The blood-oxygenation-level-dependent (BOLD) contrast method most often is used for this functional MR (f-MR) imaging application. With the initiation of neuronal activity, an increase in regional blood volume produces a net increase of intravascular oxyhemoglobin or a net decrease of deoxyhemoglobin, which is responsible for the signal increase in the area of brain activation. 36

Within observed molecules, electrons create their own magnetic response to the outer field and consequently affect the resonance frequency of their nuclei. This response of the electrons depends on the exact electronic structure of the molecule and therefore can be used to characterize different chemical substances. The size of this change in frequency (i.e., the chemical shift), depends on the strength of the interaction between the nuclei and the electron cloud. It is in the order of only a few ppm for hydrogen (lH) but up to several hundred ppm for carbon-13 (13C). The frequency components of the FID signal generated may be extracted by Fourier analysis if an investigation of different molecules containing a certain nucleus is undertaken. The result of this transformation is a plot of signal amplitude versus frequency, that is, the MR spectrum. MR spectroscopy is used to study all molecules containing nuclei with a nonzero magnetic moment, as explained previously. In organic molecules this is true for lH, 13P, and 23Na. The normal isotopes of carbon, nitrogen, and oxygen have no magnetic moments. For each of these, there are less abundant isotopes that do have magnetic moments, such as 13C. The natural abundance of 13C, however, is only 1%, which makes signal detection extremely difficult. The MR signal is proportional to the number of nuclei involved and, therefore, a measure

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of the concentration. At high fields, high-resolution MR spectroscopy is an indispensable tool in analytic laboratories. Because MR spectroscopy uses only magnetic fields and RF energies, it also can be used for the noninvasive monitoring of biochemistry in living tissue. The major problem for in vivo MR spectroscopy, however, is the exceedingly low signal intensity available for detection. This is due to the low tissue abundance of magnetic nuclei other than protons and to limitations in field strength for large-bore magnets. Proton MR imaging depends on a hydrogen concentration in water or fat of approximately 110 molar (M). Metabolite concentrations for hydrogen in other molecules, or for other nuclei, are in the millimolar (mM) or micromolar (µM) range. This explains the differences in tissue volumes that are needed to obtain equivalent MR signal intensities (e.g., 1 mm3 in lH-MR imaging, 4 mL for lH-MR spectroscopy, 27 mL for 31P-, and 690 mL for 13C-MR spectroscopy). This limitation in resolution is an important consideration for MR spectroscopy in the assessment of regional metabolism in the newborn brain. The physiologist is especially interested in the intracellular concentration of a chemical species in a particular cell type. In single-voxel MR spectroscopy, however, the measurement is an average over the sensitive volume of all tissue types. For a given tissue type, it is an average of all cell types and the extracellular space. In the brain, therefore, we generally assess a variable combination of glial cells, neuronal cells, and extracellular space, depending on the relative amounts of white matter, gray matter, and cerebrospinal fluid (CSF) contained within the volume of interest. This averaging may be overcome by using multivoxel MR spectroscopy techniques, such as chemical shift imaging (CSI). With CSI, the spectra are obtained from multiple small volumes within a large one-, two-, or three-dimentional volume of interest. These methods are limited in their practical applications because of the long acquisition times required and the rather poor resolution of the individual voxels. Furthermore, only the mobile part of a metabolite will yield an MR spectroscopy-visible signal. For example, when phospholipids are incorporated into membranes or myelin, they are not MR spectroscopy-visible. When they are broken down or synthesized, however, their phosphodiester and monoester products, or their diacyl and triacyl groups, become visible. 31P-MR Spectroscopy

In the 31P spectrum, the high-energy phosphates adenosine triphosphate (ATP) and phosphocreatine (PCr) are easily detected along with inorganic phosphate (Pi). Phosphorus atoms from other nucleotides are only present in small concentrations or are tightly bound to proteins. These give rise to low or very broad signals and often underlie the ATP resonances. From the chemical shift difference (o) between PCr and Pi in the 31P spectrum, intracellular pH can be estimated to an accuracy of about 0.1 pH units, using the Henderson-Hasselbach equation: pH

=

6.75 + loglO [(o-3.72)/(5.69-o)])

The 31P brain spectrum further exhibits two characteristically strong resonances that are of importance in the developing brain, including the phosphomonoester peak (PME) at 6.7 ppm and the broader phosphodiester peak (PDE) at 2.9 ppm. The PME consists of precursors to brain phospholipids and the PDE represents both phospholipids and their degradation products.

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1H-MR Spectroscopy

lH-MR spectroscopy contains a wide array of metabolites hidden beneath the large water resonance. Most of them overlap one another owing to the small range of chemical shift. By using water-suppression pulses, the in vivo brain spectrum reveals the following metabolites: N-acetylaspartate (NAA), creatine (Cr + PCr), choline (Cho), myoinositol (ml), glutamine (Gln), glutamate (Glu), glucose (G), taurine (Tau), and scylloinositol (scyI). Lactate (Lac) is visible only if elevated. 13C-MR Spectroscopy

For biomedical applications, it would seem important to perform carbon MR spectroscopy; however, the most abundant isotope, 12C, has no nuclear spin and therefore is not detectable by MR spectroscopy. 13C has a spin, but its natural abundance is very low (1.0%) and very little signal is available for detection. The 13C spectra, furthermore, are very complex owing to spin-spin coupling of nearby nuclei. More sophisticated techniques, such as proton decoupling, are required for their elucidation. This approach is of limited clinical use, especially in newborns, because of the RF deposition and tissue heating involved. A unique possibility for studying metabolic pathways with 13C-MR spectroscopy is to label metabolites with nonradioactive 13C (e.g., glucose labeling in glycolysis or the tricarbonic acid cycle). 43 DEVELOPMENTAL CHANGES IN THE NEWBORN PERIOD

The developing human brain is susceptible to a wide variety of insults and abnormalities. Their permanent residua vary in type and severity and their effects are manifested as dysfunctions in neurodevelopment (e.g., motor, cognitive, language, learning) and in behavior (e.g., temperament, conduct, activity level, selective attention). In recent years, MR techniques have allowed us to better visualize and understand the developmental and pathologic changes responsible for these later dysfunctions. Structural Development Assessed

MR Imaging

Cortical Development, Myelination, and Gray and White Matter Differentiation (Conventional MR Imaging and 3D-MR Imaging)

Brain imaging techniques offer objective information about the structure of the newborn brain. Using MR imaging, structural brain development (i.e., formation and maturation) has been assessed generally in a qualitative or semiquantitative way using morphologic schemes. Martin et al 62 proposed a four-stage grading system for cortical development based on the morphologic appearance of the brain surface. Stage 1 refers to the "lissencephaly" phase in which the brain surface is smooth. At stage 2, the primary gyri are defined by shallow CSF-filled sulci. At Stage 3, there is deeper infolding of the brain surface and slightly more CSF visible in the sulci. Stage 4 represents the adult pattern of well-developed tertiary gyri and deep sulci. 62 • 89 Sequential changes in graywhite matter differentiation are related to progressive alterations in the hydration and myelination of white matter, as described by several authors. 3• 5• 7• 28 • 63 • 65 The MR imaging intensities of the neonatal brain are the reverse of those seen

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Figure 1. A, Sagittal T1 spin-echo MR image (500/16) obtained in a preterm infant at 30 weeks' gestation. The immature white matter is mostly T1 hypointense, and the cortex is hyperintense. There is minimal cortical enfolding at the central sulcus (white arrow). Beginning myelination is hyperintense in the thalamic region (black arrow). There are wide extracerebral spaces. B, Sagittal T1 spin-echo MR image (500/16) obtained in a full-term infant at 40 weeks' gestation. Increased intensity is seen in the myelinated cerebral white matter compared with that seen in A, and there is increased cortical enfolding. The hyperintensity represents myelin in the internal capsule, extending into corona radiata and about the central sulcus (arrows).

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in the mature brain. The immature white matter is of lower signal intensity than gray matter on Tl-weighted images and is of higher signal intensity than gray matter on T2-weighted images. The major advantage of MR imaging over other brain-imaging techniques is not only the ability to precisely differentiate gray matter from white matter, but also to differentiate unmyelinated from myelinated white matter. These differentiations allow the in vivo assessment of brain maturation. Mature white matter is visualized on Tl-weighted images as increased signal relative to gray matter. This appearance probably is related to the increased concentration of cholesterol and glycolipids associated with the formation of myelin by the oligodendrocytes. On T2-weighted images the mature white matter is of decreased intensity relative to gray matter. This likely is related to the redistribution of extracellular water resulting from the thickening and tightening of the myelin sheaths. Myelination occurs along a caudal to rostral gradient. The spinal nerve roots and spinal cord begin to myelinate in utero during the second trimester. Toward the end of the second trimester and beginning of the third trimester, the brainstem begins to myelinate. By full term, myelination also is present in the superior and inferior cerebellar peduncles, the posterior limb of the internal capsule, the corona radiata, and about the central sulcus (Fig. 1). Quantification of observed developmental changes is necessary to precisely assess deficits or delays in cortical development and myelination. Semiquantitative MR imaging classification methods have been described"'· 65 for use in the assessment of abnormal brain development." More recently, 3D-MR imaging

Figure 1 (Continued). C, Axial T2 spin-echo MR image (3000/160) in a preterm infant at 30 weeks' gestation. The immature white matter is mostly hyperintense and the cortex is hypointense with wide Sylvian fissures. Hypointensity is noted in the perithalamic area of the posterior limb of internal capsule and represents myelin (arrows). 0, Axial T2 spin-echo MR image (3000/160) in a full-term infant at 40 weeks' gestation. Increased gyration is seen in the frontal and occipital lobes compared with that seen in C.

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Figure 2. 3-D brain model of a preterm infant (31 weeks), showing reconstruction after tissue segmentation using postprocessing techniques. The model characterizes brain surface at 31 weeks, including the precentral gyrus and the postcentral gyrus (open arrows) and the superior temporal gyrus (arrows).

methods and postprocessing techniques have been combined to allow volumetric assessment of brain development and an absolute quantitation of myelination.35· so, 77· 84 These techniques provide an accurate determination of brain volume and can be used to monitor brain growth, measure CSF volume, and quantify changes in the volume of cortical gray matter. Brain-surface morphology can be displayed in exquisite detail using 3D reconstructions and surfacerendering techniques (Fig. 2). Functional Development Assessed by MR Imaging Microstructural Development (Diffusion MR Imaging)

As explained previously, the signal attenuation of the brain on DWI is dependent on the relationship between the orientation of the white matter fiber tracts and the direction of the applied diffusion-sensitive gradients. DWI has been used to evaluate fiber-tract 11 • 73 anisotropy has been observed in cortical white matter and the optic radiations prior to any change in signal intensity on Tl- or Tl-weighted images. DWI therefore may be useful in the identification of early neurofiber development and myelination. 79· 80 Brain Activation Development (Perfusion MR Imaging)

The specific localization of brain activity as elicited by a specific function has been studied in the mature brain using techniques described previously. Visual, auditory, motor, and other tasks have been localized to specific cortical regions using £-MR imaging. Only preliminary data are available on £-MR

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imaging in the pediatric population. The development of brain function and its localization in the newborn would be of great interest. The response to visual stimulation in the newborn seems to differ from that observed in adults. An "inverted" BOLD effect has been observed in the developing brain after visual stimulation. This may indicate that brain activation in the neonate is not accompanied by a proportionate increase in cerebral blood flow. The associated increase in intravascular deoxyhemoglobin results in signal attenuation. 14• 58 Biochemical and Metabolic Development Assessed by MR Spectroscopy

The application of MR spectroscopy in the in vivo assessment of cerebral metabolism is an exciting recent development in pediatric research. MR spectroscopy has made it possible to study normal metabolite concentrations in the human brain at different developmental stages and has provided the basis for a better understanding of the pathophysiologic mechanisms in neonatal brain injury.* Energy Metabolism (31P- and 1H-MR Spectroscopy)

Neurons have poor ability to regenerate, and a continuous energy supply therefore is essential for functional integrity of the brain. Mitochondrial oxidative phosphorylation is the principal energy source for neurons. ATP is the main carrier of free energy in the brain and is hydrolyzed to adenosine-diphosphate (ADP) and Pi. The ATP:ADP*Pi ratio is an index of cellular energy reserve, i.e., the "phosphorylation potential." PCr is the stored form of high-energy phosphates from which ATP can be rapidly mobilized. With 31P-MR spectroscopy, the high-energy phosphates ATP and PCr and Pi are easily detected 19 (Fig. 3). We have shown earlier in the article that from these resonances, intracellular pH can be calculated. Age-dependent changes in these metabolites gradually occur during postnatal brain development and must be distinguished from the acute and rapid alterations associated with disease. In various studies, an age-dependent increase in the PCr:ATP and PCr:Pi ratios has been demonstrated in human newborns comparing preterm and term infants. 2• 13 These increases most likely are related to an increase in the metabolic rate associated with high-energy turnover and has been demonstrated with other methods, such as PET. 22 More recently, these metabolites have been quantified in absolute values to confirm age-dependent increases of PCr and ATP in early human brain development. 17• 21 Total Cr and PCr also can be determined by lH-MR spectroscopy48• 49 • 55 • 74 · 91 and show similar age-dependent increases. Lactate occupies a special position in energy metabolism. As an end-product of anaerobic glycolysis, the lactate concentration rises when the glycolytic rate exceeds the tissue's capacity to catabolize lactate or export it to the bloodstream. This occurs in hypoxia-ischemia and a number of metabolic disorders.25 • 94 Membrane Composition/Phospholipid Metabolism (31 P- and 1HMR Spectroscopy)

The biosynthesis of phospholipids is another metabolic pathway that can be elucidated with in vivo 31P-MR spectroscopy. The PME signal includes *References 2, 13, 17-19, 49, 50, 55, 74, 76, and 91.

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PME

PCr

y-NTP

a-NTP

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-10

Pi PDE

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0

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Figure 3. A 31 P brain MR image spectrum from a voxel centered on the thalami of a normal infant at 36 weeks' gestation. The dashed line is the result of fitting Lorentzian peak profiles to the spectrum. PME, Phosphomonoester; Pi, inorganic phosphate; PDE, phosphodiester; PCr, phosphocreatine; -y-NTP (or -y-ATP), -y-nucleotidetriphosphate; cx-NTP (or a-ATP), cxnucleotidetriphosphate; and 13-NTP (or 13-ATP), 13-nucleotidetriphosphate. (Courtesy of E. B. Cady, Department of Medical Physics and Bio-Engeneering, University College London Hospitals, NHS Trust.)

contributions from the precursors phosphorylethanolamine, phosphorylcholine, and a-glycerophosphate. The PDE signal is comprised of mobile brain phosphoglycerides, phospholipid degradation products, and sphingomyelin. The PME : PDE ratio decreases with age in the newborn up to about 70 weeks postconception. This indicates maximal phospholipid synthesis. 13• 17 Assessing the Choline signal using lH-MR spectroscopy is an indirect method for observing changes in lipid metabolism and membrane formation. The choline resonance includes contributions from various metabolites containing N(CH3 ) 3 groups. These are mostly phosphocholine and its products glycerophosphocholine and phosphatidylcholine but also metabolites like betaine and carnitine. The prominent Cho signal appearing during early brain development most likely represents the high levels of substrate needed for the formation of cell membranes and myelin. 20 • 48• 55 Amino Acid and Intermediary Metabolism (1H- and 13C-MR Spectroscopy)

N-acetylaspartate (NAA), is a free amino acid with the second highest concentration in the human CNS after glutamate. It has been shown to be uniquely localized in neuronal tissue of the adult brain. During development it also is found in oligodendrocyte precursor cells and immature oligodendrocytes.86 It, therefore, is the ideal indicator of an intact CNS. The free or nonbound NAA possibly serves (1) as a component of the aspartate pool, (2) as an acetyl group donor for the synthesis of fatty acids in myelination, and (3) as a precursor

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for, and breakdown product of, the neurotransmitter N-acetyl-aspartyl-glutamate During early brain development, the NAA increases and exhibits regional differences. The thalamus expresses increased NAA early in development, and the occipitoparietal and periventricular white matter show increases later 20• so. 55 (Figs. 4 and 5). This difference reflects the relative high density of neuronal tissue and the active myelination occurring in the thalami early in development. Intermediary metabolism involves the graded changes that cellular compounds undergo as they are transformed through chemical reactions into other molecules. Glutamate and glutamine are amino acids of intermediary metabolism. They are transformed to pyruvate, enter the Krebs cycle, serve as an energy source, and are degraded to ammonia. Changes in glutamate and glutamine concentration during development, as detected by lH-MR spectroscopy, have Cho

NAA

M-lno Cr

Full term

Glx

Cho

M-lno

NAA

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3

2

0 ppm

Figure 4. In vivo 1 H MR image spectra from a voxel centered on the thalami of a preterm infant at 31 weeks' gestation, and a full-term infant at 40 weeks' gestation. The spectra are shown in identical scaling. NAA and Cr peak increase from preterm to full-term. NAA, Nacetylaspartate; Glx, glutamate and glutamine; Cr, total creatine; Cho, choline; and M-lno, myo-inositol. (Spectra obtained at the Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, in collaboration with R. Kreis, University of Berne, Switzerland.)

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M-lno

Cho

NAA

Ch2 CH3 Tau Gluc S-lno M-lno Cho

0 ppm

Figure 5. In vivo 1 H MR image spectra from a voxel centered on periventricular white matter of a preterm infant at 31 weeks' gestation and a full-term infant at 40 weeks' gestation. The spectra are shown in identical scaling. There is a marked increase of NAA from preterm to full-term. CH2 and CH3, methylene and methyl groups; NAA, Nacetylaspartate; Glx, glutamate and glutamine; Cr, total creatine; Cho, choline; (Tau, taurine; Gluc, Glucose; and S-lno, scyllo-inositol contribute to a broad resonance that cannot be separated reliably; and M-lno, myo-inositol. (Spectra obtained at the Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, in collaboration with R. Kreis, University of Berne, Switzerland.)

not been described. Important changes in their concentrations are associated with a number of disease states, as is discussed subsequently. Another important intermediary brain metabolite is glucose. Glucose transport into the brain and absolute brain glucose concentrations have been evaluated in vivo using 13C-MR spectroscopy in adults. 43 Also, brain glucose levels can be determined in relation to the serum glucose level. The non-neurotransmitter amino acid taurine and the hexose sugar myoinositol (M-Ino) both have been shown to be important osmoregulators, particularly in the immature brain. Inositolphosphates (IP) act as second messengers in cell-to-cell signal transmission.12 The free myoinositol, a possible substrate for the formation of IP, decreases rapidly after birth, regardless of gestational age. This rapid decrease indicates a higher turnover of M-Ino postnatally. 48, 55

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MR IN THE ASSESSMENT OF NEWBORN BRAIN DISEASE PROCESSES Developmental Malformations

Current classifications of developmental and congenital malformations of the CNS are based on the gestational timing at which a noxious agent disrupts the normal sequence of neural development 88 (Table 1). With the advent of MR imaging, abnormalities once thought to be very rare brain anomalies have been shown to be common causes of neurologic disorders. 4• 71 Postnatal evaluation with MR imaging uses standard Tl- and T2-weighted images to provide excellent contrast between gray matter and white matter, CSF, and vascular structures. MR imaging is the procedure of choice for detailed delineation of CNS malformations. This is true particularly for disorders of migration and organization (Fig. 6), anomalies of histogenesis, and disorders of myelination. An equivocal prenatal ultrasound diagnosis of CNS malformation may be confirmed by ultrafast EPI techniques. These methods allow imaging of the fetus without the need for sedation or anesthesia. 57• 59• 85 Inborn Errors of Metabolism

Metabolic disorders are conditions in which an abnormality in one or more metabolic pathways results in impaired function (Table 2). These disorders

Figure 6. Neonate with cytomegaloviral infection and po\ymicorgyria. Axial T2 spin-echo MR image shows characteristic serrated appearance (arrows) of the frontoparietal perisylvian and paracentral cortex.

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Table 1. CLASSIFICATION OF CNS MALFORMATIONS BY GESTATIONAL TIMING Disorders of Dorsal Neural-Tube Development (3-4 wk) Cephaloceles Chiari malformations Spinal dysraphism* Hydrosyringomyelia Disorders of Ventral Neural-Tube Development (5-10 wk) Holoprosencephalies Agenesis septum pellucidum Optic and olfactory hypoplasia/aplasia* Pituitary-hypothalamic hypoplasia/aplasia* Cerebellar hypoplasia/aplasia Dandy- Walker spectrum Craniosynostosis Disorders of Migration and Cortical Organization (2-5 mo) Schizencephaly* Neuronal heterotopia* Agyria/pachygyria * Lissencephaly Polymicrogyria (cortical dysplasias)* Agenesis corpus callosum Disorders of Neural, Glial and Mesenchymal Proliferation, Differentiation, and Histiogenesis, (2-6 mo) M icrencephaly Megalencephaly Hemimegalencephaly Aqueductal anomalies* Colpocephaly Neurocutaneous syndromes* Vascular anomalies Malformative tumors Arachnoid cysts Encephaloclastic Processes (> 5-6 mo) Hydranencephaly Porencephaly Multicystic encephalopathy Encephalomalacia Leukomalacia Hemiatrophy Hydrocephalus Hemorrhage Infarction Disorders of Myelination (7 mo-2 yr) Hypomyelination* Delayed myelination* Dysmyelination* Demyelination* *MR imaging often or usually needed for detecflon. Modified from van der Knaap M, Valk J: Classification of congenital abnormalities of the CNS. AJNR 9:315, 1988; and Wolpert S, Barnes P: MRI in Pediatric Neuroradiology. St. Louis, Mosby-Year Book, 1992, p 84; with permission.

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Table 2. EXAMPLES OF METABOLIC AND DEGENERATIVE DISORDERS PRESENTING IN THE NEWBORN PERIOD Hypoxia-ischemia Hypoglycemia Kernicterus Amino acid and organic acid disorders Maple syrup urine disease Nonketotic hyperglycinemia Phenylketonuria Urea-cycle defects (e.g., ornithine transcarbamylase deficiency [OTC]) Pyridoxine dependency Methylmalonic and proprionic acidurias Glutaric acidurias Carbohydrate and other storage diseases Galactosemia Glycogen storage disease I Niemann-Pick Gaucher Farber Infantile sialidosis Lysosomal disorders Metachromatic leukodystrophy Krabbe Gangliosidoses (e.g., Tay-Sachs}

Respiratory oxidative (mitochondrial} disorders Leigh Menkes Mitochondrial encephalopathy with lactic acidosis and strokes (MELAS) Peroxisomal disorders Zellweger Neonatal adrenoleukodystrophy Other gray-matter disorders Neuronal ceroid lipofuscinosis Alper Other white-matter disorders Canavan Alexander Pelizaeus-Merzbacher Leukodystrophy with calfications Infantile neuraxonal dystrophy

Modified from Volpe J (ed): Neurology of the Newborn, ed 3. Philadelphia, WB Saunders, 1995, pp 515-590; and Wolpert S, Barnes P: MRI in Pediatric Neuroradiology. St. Louis, Mosby-Year Book, 1992, pp 121-150; with permission.

often are hereditary and occur at the cellular or subcellular level. Structural abnormalities shown by MR imaging often are nonspecific. For example, megalencephaly may be associated with certain metabolic diseases, including maple syrup urine disease, Canavan's disease, Alexander's disease, and the lysosomal disorders. 98 Some disorders primarily involve gray matter. These include TaySachs disease, Alpers disease, neuronal ceroid lipofuscinosis, and Menkes disease. Other diseases preferentially involve white matter, such as Canavan's, Alexander's, Krabbe's, Pelizaeus-Merzbacher's, and metachromatic leukodystrophy. Some of the disorders affecting both gray and white matter are Leigh disease, adrenoleukodystrophy, and Zellweger syndrome. The type and extent of brain involvement may be variable for the diverse disorders of amino acid and organic acid metabolism and the urea cycle defects. Migration anomalies occur in Zellweger syndrome and phenylketonuria (Fig. 7). Basal ganglia and brain-stem abnormalities often are seen with the mitochondrial cytopathies. Severe hyperbilirubinemia in kernicterus is associated with the preferential deposition of bilirubin in the basal ganglia, hippocampus, and cranial nerves. 60 It is evident that most of these disorders cannot be diagnosed conclusively by MR imaging. Newer studies have shown that MR spectroscopy can contribute to the evaluation of metabolic encephalopathies, especially for detecting intracellular abnormalities. For example, congenital lactic acidosis consists of a group of inherited metabolic disorders, including pyruvate dehydrogenase deficiency and disorders of the respiratory chain in the mitochondria. It often is difficult to diagnose these disorders because serum lactate levels often are unreliable or not representative of the metabolic defect in the CNS. It has been shown that

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Figure 7. Neonate with Zellweger syndrome. Axial proton density image shows highintensity undermyelinated cerebral white matter (arrows) and cortical pachygyria.

these disorders are associated with high cerebral lactate levels measured by lH-MR spectroscopy. 25• 3° CNS involvement in heritable disorders of oxidative phosphorylation can be diagnosed by 31P-MR spectroscopy. These show a characteristic reduction in the PCr:ATP ratio and a marked reduction of the calculated phosphorylation potential.3 4 Another inborn error of metabolism involving the CNS that has been characterized by in vivo lH-MR spectroscopy is nonketotic hyperglycinemia, a defect that causes severe encephalopathy. Glycine generates a singlet resonance peak at 3.55 ppm in the lH MR spectroscopy spectrum. Overlap of the glycine resonance with other resonances, like M-Ino, needs to be avoided by choosing longer echo times in the lH-MR spectroscopy sequence. 45 Canavan's disease is a rare autosomal recessive disorder that may present in the first few months of life with hypotonia and developmental delay. The biochemical defect associated with Canavan's disease is associated with a characteristic elevation in the NAA concentration and is easily detected and quantified by in vivo lH-MR spectroscopy.40 Ornithine transcarbamylase (OTC) deficiency is the most common defect of urea cycle metabolism and causes hyperammonemia. Condensation of high levels of ammonia with glutamic acid results in increased glutamine concentrations that are easily detected by lH-MR spectroscopy. 38 In this and other conditions, MR spectroscopy may be the first indicator of the possible pathway of a metabolic defect. Mechanisms involved in brain injury associated with hyperbilirubinemia include the failure of oxidative phosphorylation. In animal studies using 31PMR spectroscopy, it has been shown that the combination of hyperbilirubinemia and hyperosmolar breakdown of the blood-brain barrier is associated with an

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increase in Pi and a decrease of PCr. 51 Hurnan studies have to confirm these findings.

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to be performed

Several forms of intracranial hemorrhage occur in preterm and term newborns, including periventricular (germinal matrix), intraventricular, subdural, subarachnoid, and intracerebral hemorrhage. Intracerebral hemorrhage has a variable appearance on MR imaging that is related to the timing and evolution of the hemorrhage when imaged. The evolutionary process involves the sequential deoxygenation and reoxygenation of hemoglobin, the breakdown of the red blood cell (RBC), and the subsequent processing and storage of iron83 (Table 3). The process has been elucidated in detail for hemorrhage in the mature brain and adult hemoglobin. There have only been a few reports regarding the evolution of hemorrhage in the immature brain as related to fetal hemoglobin. 64 • 98 • 101 The information provided by MR imaging may define the age of the hemorrhage as to hyperacute, acute, subacute, or chronic. The hyperacute phase of hemorrhage represents the extravasation of whole blood and intact RBCs containing oxyhemoglobin. The MR imaging appearance is nonspecific and similar to water or edema. At this stage, CT scanning is more specific and shows the hemorrhage as high-density. After a matter of hours, the oxyhemoglobin is deoxygenated to form deoxyhemoglobin. In this acute phase, the hemorrhage appears T2 hypointense and is surrounded by hyperintense edema. After a few days to a week, the intracellular deoxyhemoglobin is reoxygenated and transformed into methemoglobin. In this early subacute phase, the hemorrhage appears Tl hyperintense and T2 hypointense. Following lysis of the RBCs, the hemorrhage in the late subacute phase becomes hyperintense on both Tl- and T2-weighted images while the edema is decreasing. In the chronic stages over the next several weeks to months, the methemoglobin is metabolized and the Table 3. MRI OF INTRACRANIAL HEMORRHAGE & THROMBOSIS IN THE NEWBORN BRAIN Stage Hyperacute* (+edema) Acute (+edema) Early subacute (+edema) Late subacute ( edema) Early chronic (-edema) Chronic (cavity)

Biochemical Form

Site

T1-MR Image

T2-MR image

Fe II oxyHb

Intact RBCs

lso: Low I

High I

Fe II deoxy Hb

Intact RBCs

lso: Low I

Low I

Fe Ill metHb

Intact RBCs

High I

Low I

Fe Ill metHb

Lysed RBCs (extracellular) Extracellular

High I

High I

High I

High I

Fe Ill transferrin Fe Ill ferritin and hemosiderin

Phagocytosis

lso: Low I

Low I

'CT scanning more sensitive and more specific than MR imaging or ultrasound for hyperacute/ acute hemorrhage in all compartments. RBCs, red blood cells; I, signal intensity; +, present; absent; Hb, hemoglobin; Fe II, ferrous, Fe Ill, Ferric; lso, isointense. Modified from Wolpert S, Barnes P: MRI in Pediatric Neuroradiology. St. Louis, Mosby-Year Book, 1992, p 30; with permission.

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iron is phagocytized as ferritin and hemosiderin. The latter appear as T2 hypointensities about the margins of the shrinking hemorrhage, which may further evolve to form a CSF-filled cavity or cleft. 64, 101 In the extracerebral spaces, MR imaging may detect and characterize small hemorrhages not easily shown by US. MR imaging reveals a relatively high incidence of asymptomatic subdural hemorrhages in the newborn. Dural venous sinus thromboses also are diagnosed by MR imaging but usually require MR venography to distinguish them from hemorrhages occurring along the tentorium and falx. 53 31P-MR spectroscopy has shown that energy metabolism is compromised in the adjacent tissue for weeks after a severe intraparenchymal or intraventricular hemorrhage (e.g., IVH grades 3-4). 100 The observed decrease in the PCr: ATP ratio may be attributed to various mechanisms. These may include a decrease of cerebral blood flow after IVH, an associated ischemic insult, or hypoperfusion secondary to posthemorrhagic hydrocephalus. Congenital and Neonatal Infections In the newborn, infections can be categorized depending on the gestational timing of their transmission during development. Congenital infections may alter CNS development at any stage. First- and second-trimester infections may produce malformations (see Table 1). Later infections result in encephaloclastic abnormalities. Congenital infections are acquired transplacentally or transvaginally and often are viral. The most common viruses include cytomegalovirus (CMV), rubella, and herpes simplex type IL The result of early infection may be micrencephaly, lissencephaly, polymicrogyria, or heterotopias (see Fig. 6). Late gestational infections may result in hydrocephalus (e.g., aqueductal stenosis), delayed myelination, encephalomalacia, leukomalacia, porencephaly, hydranencephaly, calcifications, or atrophy. The findings often are identified in part by US or CT scanning, but more completely by MR imaging. Toxoplasmosis is a parasitic infestation that is second in prevalence to CMV as a cause of congenital infection. It produces a necrotizing granulomatous meningoencephalitis and is characterized by calcifications and hydrocephalus easily identified by US or CT scanning. Neonatal meningitis and encephalitis may be caused by a variety of bacterial and viral infections, including Group B Streptococcus, gram-negative bacilli, and Herpes simplex type IL US or CT scanning may demonstrate ventriculitis. MR imaging may demonstrate early changes due to brain edema, infarction, or demyelination. 9

Hypoxia and lschemia

Perinatal hypoxic-ischemic brain injury is a major cause of neurologic morbidity and mortality in the neonatal period and later in childhood. Animal research has greatly expanded our understanding of some of the cellular and molecular events that accompany hypoxic-ischemia. 94, 95 Pharmacologic interventions have been postulated that have the potential to reduce or reverse such brain injury. 93 To apply these concepts to the human newborn, relatively noninvasive methods are needed to assess and monitor the complex pathophysiologic events associated with hypoxic-ischemic insults. MR imaging and MR spectroscopy have provided the possibility to assess both the early and late effects of hypoxia-ischemia on brain structure and metabolism. Most published MR imaging studies 6 have described the imaging findings

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associated with the subacute and chronic phases of the partial prolonged and profound types of hypoxic-ischemic encephalopathy (HIE). These reports have attempted to correlate the MR imaging findings with outcome. More recent studies have been directed to the early assessment of profound HIE using varied MR imaging techniques (Fig. 8). On spin-echo MR imaging, characteristic

Figure 8. Preterm infant (32 weeks' gestation) examined on day 7 of life after severe hypoxic-ischemic injury. A, Coronal spoiled gradient recalled (SPGR) (35/5/45°) MR image shows diffuse hyperintensity in the perithalamic area and globus pallidus (arrows). B, Axial T2 spin-echo MR image (3000/160) shows some loss of the normal sharp cortical hypointensity plus abnormal hypointensity in the thalami and basal ganglia (arrows). C, Axial proton density MR image (3000/36) shows similar changes in the cortical gray matter, thalami, and basal ganglia (arrows).

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abnormalities consist of Tl-hyperintensities of the deep and cortical gray matter plus overall T2-hyperintensities indicative of edema. 8 It has been hypothesized that these Tl-hyperintensities may be related to several factors, including the accumulation of lipids from the breakdown of myelin. Interesting differences are noted when comparing profound HIE in preterm and term infants. 6 The distribution of areas involved appears in part to be dependent on the stage of active myelination. For example, in the full-term infant, MR imaging often shows involvement of the perirolandic cerebral cortex that is actively myelinating. This involvement is not seen in the preterm infant. In the term newborn with profound HIE, MR imaging often also shows abnormalities involving the putamina more than the thalami. In the preterm infant, the thalami are predominantly involved. These specific findings suggest a strong correlation between the injury pattern in HIE and the stage of brain development. Actively myelinating tissues are particularly vulnerable, and the oligodendrocyte is the most likely site of injury. In 1990, Moseley et al showed for the first time that experimental ischemia causes a drop in the ADC within minutes of the insult, and that distinct regions of hyperintensity on DWI could be correlated closely with infarction on postmortem histopathologic studies. 70 DWI appeared to have demonstrated areas of ischemia at an early phase when intervention might prevent irreversible injury. The reduction in ADC with hyperacute ischemia represents reduced diffusivity in the tissue and is not associated with increased water content and signal abnormalities on spin-echo MR imaging (Fig. 9). One factor that might account for the reduction in ADC is the accumulation of intracellular macromole-

Figure 9. Preterm infant (31 weeks' gestation) examined on day 5 of life. A, Axial T2 spinecho MR image (3000/160) shows minor T2 hyperintensities and hypointensities in the periventricular white matter of an otherwise normal brain MR image. B, Axial diffusionweighted MR image (ADC map) shows bilateral areas of reduced apparent diffusion coefficient (ADC) (hypointensity) in the periventricular white matter (arrows). These areas correspond to the cystic lesions of periventricular leukomalacia detected 3 weeks later by ultrasound scanning.

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cules resulting from intracellular membrane changes as seen after free-radical injury with perioxidative attack on fatty acid moieties in cellular membranes. Another factor may be the reduction of the extracellular space by intracellular swelling (cytotoxic edema). In animal studies, it has been shown that the acute ADC reduction can be corrected by reperfusion and the reversal of ischemia. Hypothermia during reperfusion resulted in a more rapid normalization of ADC. 52 The administration of NMDA receptor antagonists and calcium channel blockers also normalized ADC values for up to half of the initial lesion size. 67 When DWI is combined with perfusion MR imaging (e.g., fast multislice EPI), cerebral blood-volume changes can be assessed both in the immediate lesion area, as depicted by DWI, and in the ischemic penumbra. 32 On follow-up DWI, the change from abnormally decreased ADC to abnormally increased ADC occurs over several hours to a few days after the initial injury. This represents the stage of evolving edema and cell lysis. These abnormalities are now visible on T2-weighted MR imaging and are usually an indicator of irreversible injury. Such observations seem to indicate that DWI may be used in the early diagnosis of acute or hyperacute perinatal HIE when other modalities (e.g., US, CT scanning, or spin-echo MR imaging) are negative or show nonspecific abnormalities 24 (see Fig. 9B). Cerebral hypoxia-ischemia severe enough to produce irreversible tissue injury is always associated with major perturbations in the energy status of the brain. Alterations occur not only in the adenine nucleotides but also in PCr and precede changes in ATP, ADP, and AMP. 31P-MR spectroscopy allows the study of early and late disturbances of energy metabolism associated with hypoxiaischemia.47· 99 The PCr : Pi ratio falls to a minimum value after the hypoxicischemic insult, and its value correlates with the severity of long-term functional impairment. Simultaneously, the Pi: ATP ratio starts to rise and is an indicator of the failure of steady-state energy metabolism. A decrease in PCr is the first sign of increased energy expenditure as the cell tries to maintain ATP by transferring phosphorus from PCr to ADP. Although the PCr: ATP ratio tends to be lower in severely asphyxiated newborns, it is the rise in Pi, a measure of the failure of the oxidative phosphorylation, that predicts the outcome (Fig. 10). This is revealed primarily by the Pi : ATP ratio.'· '8 · 69 The loss of cellular ATP during hypoxia ischemia severely compromises those metabolic processes that require energy for their completion. The failure of the ATP-dependent Na-K pump causes an intracellular accumulation of Na and CL The resulting net increase in intracellular water (cytotoxic edema) is visualized with DWI. When oxidative phosphorylation is impaired, energy metabolism follows the alternate route of anaerobic glycolysis and produces lactic acid. Lactate has a chemical shift of 1.3 ppm and appears as a doublet peak due to coupling effects on lH-MR spectroscopy. Groenendal et al first described markedly elevated lactate levels in five infants with severe perinatal asphyxia. All of them died within the neonatal period.42 Recently, lH-MR spectroscopy data has been generated that demonstrates regional differences in lactate elevation after hypoxic-ischemic events in newborns. Single-volume lH-MR spectroscopy in these patients showed a greater increase of the Lac : NAA ratio in the thalamus and basal ganglia than in the occipitoparietal cerebrum.76 These findings suggest that lactate elevations are particularly pronounced in areas of high metabolic turnover during a specific time of development. This corresponds to the abnormalities demonstrated on MR imaging in profound HIE (see Fig. 8 A-C). As markers of cell integrity, other metabolites visible on lH-MR spectroscopy can be used for the assessment of HIE. NAA, the amino acid specific to neuronal cells and oligodendrocyte precursors, is one such marker. Reports on

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PME a -NTP

10

5

0

-5

-10

~

-NTP

-15

ppm

Figure 10. A 31 P brain MR image spectrum from a term infant after severe birth asphyxia. The dashed line is the result of fitting Lorentzian peak profiles to the spectrum. The spectrum is dominated by a markedly increased P; peak with both the PCr and the NTP resonances being reduced (compared with the normal spectrum shown in Fig. 4). PME, Phosphomonoester; Pi, inorganic phosphate; PCr, phosphocreatine; -y-NTP (or -y-ATP), -ynucleotidetriphosphate; rr-NTP (or rr-ATP), rr-nucleotidetriphosphate; [3-NTP (or [3-ATP), [3nucleotidetriphosphate. (Courtesy of E.B. Cady, Department of Medical Physics and BioEngineering, University College London Hospitals, NHS Trust)

adult stroke have stressed the importance of the loss of NAA as an indicator of irreversible cell damage. 16' 29 These findings also were observed in cases of neonatal infarction using chemical shift imaging such that regions of low NAA : Cho ratios corresponded to the later development of cysts. 41 In some reports of HIE, varied results were obtained regarding the NAA, depending on the timing of the lH-MR spectroscopy procedure. In general, early assessments showed no significant decreases in the NAA: Cho and NAA: Cr ratios. Assessments 1 to 2 weeks after the insult, however, showed good correlation between the decreased NAA: Cho ratio and the severity of the HIE 41 , 42, 75 , 76 (Fig. 11). It is believed that glutamate neurotoxicity plays a key role in acute and delayed hypoxic-ischemic damage to brain cells. Glutamate is visible on lH-MR spectroscopy, though its quantitation is difficult due to its high coupling and multiple resonances (see Fig. 11). In a recent study of children with HIE owing to near-drowning, lH-MR spectroscopy showed early increases in glutamate and glutamine. Increased lactate and a persistently decreased NAA also were seen. 54 In this report, the prognostic index based on lH-MR spectroscopy showed a 90% sensitivity and 100% specificity for outcome. These and other studies have clearly shown that HIE may evolve over several days and result in further neuronal and glial cell death (i.e., apoptosis). Medical interventions during this period might alter the course of hypoxicischemic damage. Interventions that have been widely studied, especially in animal research, include (1) hypothermia to reduce the postischemic energy demand, (2) hyperosmolar agents to reduce the cerebral edema, (3) oxygen-freeradical scavengers to protect cellular membranes against peroxidation, (4) exci-

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CH2 CH3 Lactate

Cho

HIE:Preterm

Cho

M-lno

NAA Cr

4

3

2

0

Figure 11. In vivo 1 H MR image spectra from a voxel centered on thalami of a preterm infant at 31 weeks' gestation with severe hypoxic-ischemic encephalopathy (HIE) and a normal preterm infant of the same gestational age. The spectra are shown in identical scaling. In the preterm infant after HIE, there is a marked increase in lactate, increased methylene and methylgroup resonances, a complete loss of the NAA resonance, and increased resonance in the area of Glx. CH2 and CH 3 , methylene and methyl groups; Lactate, NAA, N-acetylaspartate; Glx, glutamate and glutamine; Cr, total creatine; Cho, choline; and M-lno, myo-inositol. (Spectra obtained at the Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, in collaboration with R. Kreis, University of Berne, Switzerland.)

tatory amino acid antagonists (e.g., glutamate receptor blockers) to protect against glutamate induced cell lysis, and (5) calcium channel blockers to stop the activation of lipases, proteases, and endonucleases within the injured cell. MR imaging and MR spectroscopy are ideal in vivo methods to monitor these potential treatment interventions. Correlations with Neurndevelopmental Outcome

The main advantage of MR imaging over other imaging modalities is its ability to assess brain development under normal conditions and in association with brain injury. Correlations between neurodevelopmental delay and delay in myelination, either qualitative or by staging systems, have been widely reported.26· 28 • 37• 61 • 90 Other reports have addressed whether MR imaging findings were predictive of neurodevelopmental outcome. 27• 31 • 46• 66 • 82• 87 In one report, preterm infants with delayed myelination at 44 weeks' gestation were shown to

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have an increased risk for neurodevelopmental delay at 1 year of age. 44 In another report, lesion size after perinatal infarction was not predictive of the presence or severity of hemiplegia. 15 With currently available neonatal intensive care technology it has become very important to make an early determination of the impact of brain injury on later neurodevelopmental outcome. Conventional clinical parameters often are unreliable prognostic indicators in the first few days of life, especially in neonates with HIE and those who are sedated with anticonvulsants. Conventional MR imaging has been shown to be of limited value in the early assessment of the final extent of injury. The possibility of using MR spectroscopy as an additional early source of information in predicting outcome has been addressed in several recent studies.7, 42, 69 , 75, 78 31P-MR spectroscopy performed during the first week of life has shown that the PCr:PI and Pi:ATP ratios in asphyxiated newborns with an adverse outcome differ significantly as compared with asphyxiated newborns with a normal outcome and nonasphyxiated newborns. 69 ' 78 An abnormal 31P-MR spectroscopy in the first week of life has a high specificity and a high positive predictive value for poor outcome. Because of the limited sensitivity of the single-voxel method, however, normal PCr: Pi or Pi: ATP ratios were clinically less helpful. 1 31P-chemical-shift multivoxel imaging may be used to improve the sensitivity. 39 lH-MR spectroscopy also may contribute to outcome prediction in newborns with HIE. Low NAA:Cho and NAA:Cr ratios have been shown to correlate with adverse outcomes. 42, 75 A more recent study showed that an early elevation of the Lac : NAA ratio above the 95% confidence interval correlates with death or a major disabling impairment at 1 year of age. Most of these patients had mild to moderate signs of clinical HIE according to the Sarnat staging. 76 These findings indicate the potential value of MR spectroscopy to assess early changes in brain metabolism associated with early HIE and their consequences for later neurodevelopmental outcome. Further investigations are needed to design MR spectroscopy protocols that can be applied routinely in the evaluation of the newborn brain. SUMMARY

MR imaging provides unequaled sensitivity as compared with US or CT scanning for evaluating developmental changes and pathologic processes in the newborn brain. Myelination can be assessed qualitatively and quantitatively using newer 3D-MR imaging methods. MR imaging provides a much clearer delineation of many developmental disorders, including anomalies of migration and organization, as well as a variety of metabolic disorders and congenital infections. Neonatal intracranial hemorrhage is detected in all its locations by MR imaging. The timing of the hemorrhage is a unique feature of MR imaging. Venous thrombosis also can be identified by MR imaging and confirmed with MR angiography. HIE is the major cause of potentially preventable or reversible brain injury that results in considerable long-term neurologic morbidity. Early detection is crucial for interventions aimed at preventing or reversing ongoing injury. DWI can show early changes at the cellular level that are not detectable by any other imaging modality. MR spectroscopy has further opened the possibility of studying the metabolic mechanisms that define the pathophysiologic events taking place in neonatal brain injury. Both 31P-MR spectroscopy, as a marker of the acute changes in energy metabolism, and lH-MR spectroscopy, with the measurement of lactate

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and the excitotoxic aminoacids glutamate and glutamine, have enabled us to study the early and late effects of insults to the newborn brain in a noninvasive fashion. Studies performed to determine the predictive value of MR spectroscopy for later neurodevelopmental outcome after HIE have shown promising results but need further evaluation on larger patient samples. The potential use of these methods in the evaluation of early neuroprotective treatment regimens in the newborn remains to be determined.

ACKNOWLEDGMENT The authors are thankful to Virginia Grove for her help in preparing this manuscript.

References 1. Azzopardi D, Wyatt ], Cady E, et al: Prognosis of newborn infants with hypoxicschemic brain injury assessed by phosphorus magnetic resonance spectroscopy. Pediatr Res 25:445-451, 1989 2. Azzopardi D, Wyatt J, Hamilton P, et al: Phosphorus metabolites and intracellular pH in the brains of normal and small-for-gestational age infants investigated by magnetic resonance spectroscopy. Pediatr Res 25:440-444, 1989 3. Ballesteros M, Hansen P, Soila K: MR Imaging of the developing human brain: IL Postnatal development. RadioGraphics 13:611-622, 1993 4. Barkovich A, Kjos B: Non-lissencephalic cortical dysplasia: Correlation of imaging findings with clinical deficits. Am J Neurorad 13:95-103, 1992 5. Barkovich A, Kjos B, Jackson D, et al: Normal maturation of the neonatal infant brain: MR-imaging at l.5T. Radiology 166:173-180, 1988 6. Barkovich A, Sargent S: Profound asphyxia in the premature infant: Imaging findings. AJNR Am J Neuroradiol 16:1837-1846, 1995 7. Barkovich A, Truwit C: Practical MRI Atlas of Neonatal Brain Development. New York: Raven, 1990, pp 3-52 8. Barkovich A, Westmark K, Partridge C, Sola A, Ferriera D: Perinatal asphyxia: MRfindings in the first 10 days. AJNR Am J Neuroradiol 16:427--438, 1995 9. Barnes P, Young Poussaint T, Burrows P: Imaging of pediatric central nervous system infections. Neuroimaging Clinics of North America 4:367-390, 1994 10. Basset P, Pierpaoli C: Microstructural and physiological features of tissues elucidated by guantitative-diffusion-tensor MRI. J Magn Reson B 11:209-219, 1996 11. Belliveau J, Ke1medy D, McI
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